There are multiple types of nicotine acetylcholine receptors (nAChR) in the brain associated with synaptic function, signal processing, or cell survival. The therapeutic targeting of nicotinic receptors in the brain will benefit from the identification of drugs which may be selective for their ability to activate or inhibit a limited range of these receptor subtypes. Mecamylamine is a ganglionic blocker developed many years ago as an antihypertensive and more recently suggested to be useful as a component in the pharmacotherapy for Tourette's syndrome (Sanberg, P. R. et al., Lancet, 1998, 352:705-706) and smoking cessation (Rose, J. E. et al., Clin. Pharmacol. Ther., 1994, 56(1):86-99). However, electrophysiological characterization of mecamylamine has shown it to be relatively nonselective (Papke, R. L. et al., J Pharmacol Exp Ther, 2001, 297(2):646-56), consistent with the observation that it effectively blocks all of the peripheral and central nervous system (CNS) effects of nicotine (Martin, B. R. et al., Med. Chem. Res., 1993, 2:564-577).
A family of bis-tetramethylpiperidine compounds have been identified as inhibitors of neuronal-type nicotinic receptors (Francis, M. M. et al., Biophys. J., 1998, 74(5):2306-2317). The prototype compound in this series is bis-(2,2,6,6-tetramethyl-4-piperidinyl)-sebacate (BTMPS or Tinuvin 770), which produces a readily reversible block of muscle-type nAChR and a nearly irreversible use-dependent, voltage-independent block of neuronal nAChR. The tetramethyl-piperidine groups of BTMPS are sufficient to inhibit nAChR, and the conjugation of two such groups by a long aliphatic chain accounts for both the selectivity and slow reversibility of BTMPS inhibition of neuronal nAChR (Francis, M. M. et al., 1998).